SE452110B - MULTILAYER PROTEST MATERIAL AND PROCEDURE FOR ITS MANUFACTURING - Google Patents

Description

452 110 is prepared from a solution of a copolymer in a mixed solvent and coating of a substrate of uniform thickness of such solution. The polymer is precipitated by evaporation and one or more successive layers are applied to form a prosthetic material.

The invention is based on a completely new idea with the use of a mixed solvent and special precipitation technology. The mixed solvent comprises as a first component a fluid which is miscible with the solvent but acts as a precipitating non-solvent with respect to the polymer.

The mixed solvent further comprises a second component, which is the solvent for the polymer. In the polymer solution, using a mixed solvent, two criteria are important, which are further explained below. In The first criterion concerns. the solution of polymer in the mixed solvent is characterized in that the solvent component thereof must have a higher evaporation rate than the non-solvent component. the following.

The second criterion concerns. the polymer solution of the mixed solvent is characterized in that the degree of saturation thereof with respect to the polymer content must be such that the polymer solution is close to the point of precipitation.

The significance of this feature is explained in By a saturation "close to the point of precipitation" is meant that the polymer solution used to prepare the mono- or multilayer material contains at least about 60% and preferably at least about 80% by weight of the amount of polymer corresponding to a saturated solution of the same polymer in the same mixed solvent. It is preferred that the polymer solution used in the process of the invention does not contain less than about 90% of said amount of polymer.

In addition to these features of the polymer solution used to make the multilayer prosthetic material, the invention also provides a new precipitation technique which basically consists in precipitating the substrate coating of polymer solution by evaporating at least a part of the solvent component or solvent fraction in the mixed solvent medium. for precipitating the polymer to form a layer thereof on the substrate before applying an additional layer of polymer solution. The evaporation of the solvent component in the mixed solvent is facilitated by the fact that the solvent component is more volatile than the non-solvent component in the mixed solvent.

The evaporation of the solvent fraction from the mixed solvent can be achieved in any suitable manner.

Evaporation can thus take place only by self-evaporation in ambient air or it can be accelerated by heating, forced circulation, application of vacuum or with the use of some other conventional technique. According to the invention, the evaporation of the solvent component is carried out to a point where a certain amount of solvent component is left in each preceding layer when the subsequent layer is applied. It has been found that if the evaporation takes place in this way, repetition of the procedure to form an additional layer of material results in the formation of a fibrous boundary layer structure in the area between the layers, which forms a mechanically strong bond between the first layer and the subsequent layer. delamination of eg a graft wall during implantation in a living body. Such delamination is to the detriment and generally results in the formation of extensive aneurysms in this way, successive implantation is avoided.

Although the invention is not limited to any specific theory or mechanism, there are various factors that can explain It has thus been observed that in the boundary layer between the two on each other how the very strong bond is achieved. The following layers contain many fibers which appear to be interconnected, probably due to the fact that many small fibers in the outer surface of the first layer are partially dissolved in the mixed solvent system. As soon as the new fibers are precipitated in the subsequent evaporation step, the partially dissolved fibers formed in the previous step are also formed again, so that a mutual reading effect is formed between the two successive layers. There are also fibers precipitated in the second subsequent layer, which are enclosed in the pores of the first layer. Finally, there may also be some form of gluing effect between the fibers in the outer surface of the first layer and the inner surface of the second layer.

This results from the presence of small amounts of solvent left in the precipitated polymer.

There are, of course, alternative procedures for preparing a polymer solution using a mixed solvent which is close to the point of precipitation.

One such option that is easy to use in practical application is as follows. A solution of the polymer is prepared using a solvent, eg tetrahydrofuran.

To this clear polymer solution is added a precipitating agent or non-solvent, for example water, until a light tetrahydrofuran is then added to the cloudy solution until a clear solution again becomes cloudy. is obtained, and this clear solution is useful for coating a substrate and meets the requirements of the present invention with respect to proximity to the precipitation point.

According to the present invention, it has been found that by using the technique outlined above, a polymer layer is obtained by precipitation, which has a fiber-like structure. The precipitated fiber-like material consists of fibers of different thicknesses from clay. Each precipitated layer has a thickness of e.g. , 01-l mm, and up to about 100 and whose pores are interconnected. fibers to relatively thick ones. Empty. more layers can be applied in subsequent operations to provide a multilayer prosthetic material of desired mechanical strength. structure, the prosthesis wall is strong, highly compliant and mechanical Due to the fiber-like porous compatible with the tissue to be replaced. Although the polymer concentration of the mixed solvent solution is not critical to obtaining useful results, it is preferable to use a solution containing less than about 5% by weight of polymer. In some cases the concentration may be less than about 3% polymer and in some cases may even concentrations as low as about 0.5% or less may be useful.

In connection with or after the coating of the substrate with the polymer solution, the applied solution is precipitated by evaporating at least a part of the solvent fraction in the mixed solvent. The procedure is then repeated as desired to form a multilayer product.

It has been found that the pore size is highly dependent on the concentration of the polymer solution. An example of the relationship between pore size and polymer concentration for a given copolyurethane is given below.

Concentration Average pore size weight percent um 0.20 '300-500 1.00 100-300 1.25 50-150 1.45 35- 60 2.00 30- 50 4.00 5- 15 By using the multilayer precipitation technique according to the invention as described above it is possible to produce a multilayer prosthesis wall for replacement of tissue with different pore sizes in the different layers. In eg a vascular prosthesis it is possible to form the inner layers, eg the layers of the lumen of the prosthesis, with a relatively small pore size (5-10 μm) to promote endothelialization, but the central layers with a relatively large pore size ( 30-100 μm) to achieve good tissue growth.

In the process of the present invention, the polymer used to prepare the substrate coating solution may be any polymer useful in the context, but it is preferred to use a copolyurethane, especially a block or block copolyurethane.

The technique according to the present invention enables easy production of multilayer products with different medium pore sizes in the individual layers. This is achieved by varying the concentration of polymer in the casting solution, ie the This is useful eg for the production of a vascular prosthesis, where it is solution that is applied to the substrate. it is desirable to have the lumen surface of the prosthesis with a much lower pore size, such as in the range of about 5-15 μm. This facilitates endothelialization after implantation. On the other hand, it is desirable that the remaining portion of the prosthesis wall have larger pores to allow faster tissue growth. As the solvent, any solvent capable of dissolving the general polymer can be used, but preferred solvents are those selected from the group consisting of tetrahydrofuran, amide solvents and sulfoxide solvents. Among such solvents may be mentioned in addition to tetrahydrofuran (THF), dimethylacetamide (DMAC), dimethylformamide (DMF) and dimethylsulfoxide (DMSO). Especially preferred is a mixed solvent of THF and DMF.

Any non-solvent capable of precipitating the polymer can be used as the non-solvent. A preferred liquid in this respect is water, but also lower alkanols, such as ethanol, can be used, possibly. in combination with water. a) The polymer used in the formation of the solution should be biocompatible and elasticity is preferred in certain applications, such as use in vascular prostheses. The polymer can be natural or synthetic. Ex. on the former are polyamino acids (eg polyglycine), polysaccharides (eg cellulose derivatives, alginates). Ex. on synthetic polymers are silicones and polyurethanes. Mixtures of different polymers can also be used.

As previously indicated, aliphatic block polyurethanes or aromatic block polyurethanes can be used in the practice of the art of the present invention. To obtain materials which are non-toxic, non-mutagenic and non-carcinogenic, it is preferable to use aliphatic block polyurethanes or using another term aliphatic block copolymers.

The polymeric material for use in the invention can be conventionally prepared from aliphatic polyurethanes based on diisocyanates, for example 1,2-diisocyanate, 1,1'-diisocyanate pentane, hexamethylene diisocyanate, methane diisocyanate pentane, 1,9-diisocyanate nanocyanate, 1,8-diethanocyanate , 1,4-diisocyanate butane, 4,4'-methylenebicyclohexyl diisocyanate, lysine diisocyanate, 1,4-trans-cyclohexane diisocyanate, dimethyl diisocyanate silane, diethyl diisocyanate silane. In addition to such diisocyanates, polyols having an average molecular weight in the range of 500-10,000 can be used, for example poly (ethylene adipate), poly (tetramethylene adipate), poly (1,4-cyclohexyldimethylene adipate), poly (hexamethylene oxalate), poly (hexamethylene glutarate) , poly (E-10 15 20 25 30 35 452 110 aprolactone), poly (tetramethylene oxide), poly (ethylene oxide), poly- (1,2-propylene oxide). Chain extenders, eg 1,4-butanediol, 2,4,6-tris (dimethylaminomethyl) phenol, glycerol, 3,6-dioxooctane-1,8-diol, ethylenediol, diethylenediol, tetramethylenediamine, ethylenediamine, hexamethylenediamine, propylenediamine The copolyurethanes are conventionally formed by, for example, reacting a prepolymer, such as a polyether diol, with a diisocyanate, and the product resulting from such a reaction can then be chain extended by reaction with a diol or diamine. By such polymerization process, copolymers can be prepared with preferred molecular weights and preferred viscosity in solution. By varying the molecular weight and thus the viscosity of the polymer in solution, the degree of degradation and porosity of the material produced can be controlled.

The selected polymeric material is dissolved in a suitable solvent of the type indicated above, and the proportions of polymer and solvent are suitably selected to form the desired percentage of solids in the solution formed. The coating solution was then used to coat a substrate to form an original coating of uniform thickness. As the substrate, any mechanical device of a suitable type can be used, such as a metal plate or a metal mandrel, preferably coated with a resistant plastic, such as polytetrafluoroethylene. The coating can be accomplished by spraying, extrusion, dipping or immersion or by any other conventional means.

The multilayer prosthetic material of the present invention can be used in a variety of medical applications.

It can thus be used as a vascular graft, as a skin graft or as a wound compress. In addition, it can be used as elastic membranes for replacement of eardrums, as an element for orthopedic surgery and as an anticoagulant tube for blood transfusion. b) For use in a graft or a wound compress, a multilayer composite material can be selected, wherein the inner and / or the outer layer consists of a porous degradable polymer, eg polyhydroxybutyrate or a polysaccharide to improve endothelial formation resp. epithelial formation. The invention will now be further described by means of concrete examples, which, however, may not be construed as limiting the scope of the invention.

EXAMPLE 1 - General Procedure Preparation of Casting Solution Segment polyurethane was dissolved in dimethylformamide (DMF) at 23 ° C (2% by weight) solution and then precipitated with water to remove oligomeric fractions thereof.

Precipitated polymer was dried to constant weight and then dissolved in tetrahydrofuran (THF). polymer in the solution was in the range of 0.1-4% by weight. In general, more concentrated solutions are required for the preparation of the Concentration Wave depending on the purpose for which the solution is used. reinforced vascular prostheses, while more dilute solutions are required for the production of, for example, wound compresses or artificial skin.

The polymer solution formed was heated to Z5 ° C and water was then added dropwise while stirring the solution vigorously.

The amount of water that can be added to the polymer solution at the given temperature without causing precipitation of the polymer depends, among other things, on the molecular weight and the molecular weight distribution of the polyurethane used and the concentration of polymer in the solution.

In general, less water (non-solvent) can be added to a solution made from a polymer having a high molecular weight and a wider molecular weight distribution.

The presence of water in the polymer solution affects the porosity of the product formed. It has been found that the more water added to the polymer solution, the larger the pores are formed. From the various polyurethane solutions described in this example, various medical products can be prepared, eg vascular prostheses, wound compresses, microporous patches, etc.

These products can be produced by commonly used techniques, eg dip coating, spraying, painting, brush application, sheet coating, etc.

The products can be produced in one operation or in several similar operations, for example for the production of vascular prostheses composed of several layers with different porosities.

Application of the polymer solution to the substrate results in rapid precipitation of polymer, which is due to evaporation of solvent from the ternary system of polymer solvent-non-solvent system.

It has been found to be preferable to, after depositing the polymer layer on the substrate, wipe or press off solvent from this layer before depositing the subsequent layer on the previous one. This measure contributes to the formation of strong mechanical bond between the layers that form the structure of the product and facilitates the avoidance of separation of the layers after implantation.

EXAMPLE II Preparation of Vascular Prostheses Polyether urethane prepared according to the procedure UPP 'was dissolved in tetrahydrofuran to form a solution with one of the same as in Ex. In the above with a molecular weight of 1.0 x 105 concentration of about 2% by weight.

The polymer solution was heated to about Z5 ° C, after which about 20% by weight of water (based on the total volume of solvent) was added to the solution with stirring.

Stainless steel bars covered with polytetrafluoroethylene (PTFE) were dip coated with the polymer solution, and about 5 minutes. later, excess solvent-non-solvent was removed from the polymer precipitate by applying to the polymer layer an absorbent paper. The dip coating procedure was repeated 40 times to form a composite, mechanically strong and highly elastic vascular prosthesis.

The prostheses on the molds were soaked for 16 hours in deionized water, then removed from the mold and soaked again for 5 hours. The prostheses were dried at 40 ° C in a vacuum oven before sterilization with ethylene oxide.

Prostheses prepared in this way show satisfactory low thrombogenic activity, rapid endothelial formation and regular tissue growth when implanted in pigs.

EXAMPLE III Preparation of a microporous polyester urethane having an average molecular weight of 3.0x patch (artificial dermis) based on hexamethylene diisocyanate, poly (ethylene adipate) and 14-butanediol was dissolved in a mixture of tetrahydrofuran-dimethylformamide (9 .8 / 0.2 vol / vol) to form a polymer solution with a polymer concentration of 0.7% by weight.

The polymer solution was stirred, heated to 28 ° C, after which 20% by volume of water (based on the total amount of solvent) was added dropwise to the solution.

The polymer solution was sprayed onto polished PTFG plates.

The formed macroporous patches were finally soaked for 16 hours in deionized water and then dried.

The macroporous patches with a porosity in the range of 100-150 μm were used to cover full thickness skin lesions. the healing process of non-infected wounds.

EXAMPLE IV ARTIFICIAL SKIN Polyether urethane based on hydrolytically stable cyclo- It was found that this treatment stimulates drug-aliphatic diisocyanate (TexoflexR-80a] dissolved in a tetrahydrofuran-water mixture (99 / l v / v). polymer in the mixture was 0.75% by weight.

Concentrate The polymer solution was sprayed against it in e.g. III described microporous polyurethane patch.

As a result of the spraying, a two-layer membrane composed of an upper protective layer with a porosity in the range 0.4-0.9 μm and a lower layer with a porosity in the range 100-150 μm was formed.

This composite membrane is non-toxic, non-mutagenic and non-carcinogenic.

The two-layer membrane was used to cover donor sites and full-thickness skin lesions in guinea pigs. It was found that the membrane satisfactorily protects against bacterial penetration and ensures proper water and gas transport to and from the wound. The use of the membrane facilitates the healing process for non-infected guinea pig wounds.

Claims (14)

11 fl452 110 PATENT REQUIREMENTS A method of making a multilayer prosthesis for use with a living body, said material exhibiting mechanical compliance with soft tissue and possessing biocompatibility, which method is characterized by the steps of: a) making a polymer solution using a mixed solvent, said solution being close to its point of precipitation and wherein the mixed solvent consists as a first component of a fluid which is miscible in said solvent but acts as a precipitating non-solvent with respect to the polymer, and further consists of as a second component a solvent for the polymer, said second component having a higher evaporation rate than said first component; b) coating a substrate and precipitating thereon of polymer pure to form a physically stable porous structure by evaporating at least a portion of the solvent fraction in the mixed solvent, the evaporation being carried out to a state where a certain amount of solvent is left in each continuous layer when the subsequent layer is applied, after which this step is repeated as needed to form a multilayer material. - Process according to claim 1, characterized by the use of a copolyurethane in step a). A method according to claim 2, characterized in that the polymer is a block copolyurethane. ....._..__..._._.: __._....,> ._ ---___. , v. ßlá -... snél-: ååan __, _ Process according to any one of the preceding claims, characterized in that the solvent is selected from the group consisting of tetrahydrofuran, amide solvent and sulfoxide solvent. Process according to any one of the preceding claims, characterized in that the non-solvent is selected from water and lower alkanols. Process according to any one of the preceding claims, characterized in that by varying the concentration of polymer in the solution in step a) a multilayer material is produced, wherein the different layers have different average pore sizes. 452 110 12 Process according to one of the preceding patent claims, characterized in that the solution prepared in step a) contains less than about 5% by weight and in particular less than about 3% of polymer. A multilayer prosthetic material for use in a living body, said material exhibiting mechanical compliance vis-à-vis soft tissue and possessing biocompatibility, produced by the method according to any one of the preceding claims, characterized in that it is composed of a plurality of porous layers of block copolyurethane. interconnected by bridging fibers connected to the respective adjacent layers. Material according to claim 8, characterized in that the different layers have different average pore sizes. (0. Material according to claim 8 or 9 in the form of a vascular graft, a skin graft or a sarcoma. Material according to claim 8, 9 or 10, characterized in that the thickness for each layer is about 0.01 - 1 mm. Material according to any one of claims B-11 containing up to about 100 layers. Material according to any one of claims B-12, characterized in that the pore size is in the range of about 1 - 100 .mu.m. Material according to claim 8 in the form of a sarcoma compress, characterized in that it is composed of a first degradable porous membrane facing the wound and a second non-degradable protective membrane membrane which allows fluid transport and prevents bacterial penetration.